rs786205452

Positions:

• chr1-216175450-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_206933.4(USH2A):​c.4429G>T​(p.Gly1477Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.08

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-216175450-C-A is Pathogenic according to our data. Variant chr1-216175450-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-216175450-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.4429G>T	p.Gly1477Ter	stop_gained	21/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.4429G>T	p.Gly1477Ter	stop_gained	21/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.4429G>T	p.Gly1477Ter	stop_gained	21/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000366942.3	c.4429G>T	p.Gly1477Ter	stop_gained	21/21	1		ENSP00000355909
USH2A	ENST00000674083.1	c.4429G>T	p.Gly1477Ter	stop_gained	21/73			ENSP00000501296

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	36
DANN	Benign	0.97
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	A;A;D
Vest4		0.86
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786205452; hg19: chr1-216348792; COSMIC: COSV56433659;